Takaisin Tulosta

Ischaemic stroke and myocardial infarction risk with oral contraceptives

Evidence summaries
Heidi Alenius
4.11.2015

Level of evidence: B

Risk of ischaemic strokes and myocardial infarction appears not to be increased in non-smoking women aged less than 35 years and using low dose combined oral contraception (COC) compared with non-users. However, in smoking women over age of 35 years and using COC the absolute risks appears to be multifold. Cardiovascular mortality associated with smoking appears to be significantly greater than that associated with COC use at all ages.

A systematic review «Gillum LA, Mamidipudi SK, Johnston SC. Ischemic st...»1 including 16 studies was abstracted in DARE. Current oral contraceptive (COC) use was associated with increased risk of ischaemic stroke. Studies that did not control for smoking (P=.01) and those using hospital-based controls (P<.001) found higher risk ratios (RR). Stroke risk was not associated with past use of COC. Smaller estrogen doses were associated with lower risk (p=0.01 for trend). The summary RR was 1.93 (95% CI 1.35-2.74) for low-estrogen (< 50 μg) preparations in population-based studies that controlled for smoking and hypertension. This translates to an additional 4.1 ischemic strokes per 100,000 nonsmoking, normotensive women using low-estrogen COC, or 1 additional ischemic stroke per year per 24,000 such women.

A Cochrane review «»1 «Roach RE, Helmerhorst FM, Lijfering WM et al. Comb...»5 included 24 case control studies estimating the risk of myocardial infarction or ischemic stroke in users compared with non-users of different types, doses and generations of combined oral contraception (COC) by a network meta-analysis. COC users were not at increased risk of myocardial infarction or ischemic stroke compared with non-users (OR 1.0, 95% CI 0.9 to 1.0). These ORs were similar for myocardial infarction alone (odds ratio, OR, 0.9, 95% CI 0.8 to 1.0) and ischemic stroke alone (OR 1.0, 95% CI 0.9 to 1.1). The risks did not vary according to the generation of progestagen or according to progestagen type. However, the risk of myocardial infarction or ischemic stroke was only increased in women using COCs containing ≥ 50 µg of estrogen.

According to the EMA’s Pharmacovigilance Risk Assessment «The EMA’s Pharmacovigilance Risk Assessment...»2 the risk of arterial thromboembolism (ATE, blood clots in arteries, which can potentially cause a stroke or heart attack) is very low. There is no evidence for a difference in the level of risk between products depending on the type of progestogen.

In a 15-year Danish historical cohort study «Lidegaard Ø, Løkkegaard E, Jensen A et al. Thrombo...»3, nonpregnant women (15-49 years), with no history of cardiovascular disease or cancer were followed. Data on use of hormonal contraception, clinical end points, and potential confounders were obtained from Danisih national registries. A total of 1 626 158 women contributed, 3 311 thrombotic strokes (21.4 per 100 000 person-years) and 1725 myocardial infarctions (AMI) (10.1 per 100 000 person-years) occurred. Relative risks were calculated for contraceptives with ethinyl estradiol (EE) at a dose of 30 to 40 μg and different progestin types as well as for EE at a dose of 20 μg and different progestins. Although the absolute risks of thrombotic stroke and AMI associated with the use COC were low, the risk was increased by a factor of 0.9 to 1.7 with COC that included EE at a dose of 20 μg and by a factor of 1.3 to 2.3 with those that included EE at a dose of 30 to 40 μg, with relatively small differences in risk according to progestin type.

In a hospital-based case-control study «Farley TM, Meirik O, Chang CL et al. Combined oral...»4 in UK, among women who did not use COC, smoke nor had any other cardiovascular risk factors total incidence of stroke and AMI were less than 2 events per 100 000 woman years in those aged 20-24 years and rose exponentially with age to 8 events per 100 000 among women aged 40-44 years. Cardiovascular mortality associated with smoking was greater than that associated with COC use at all ages. Attributable risk associated with COC use was 1 death per 370 000 users annually among women aged 20-24 years, 1 per 170 000 at ages 30-34 years, and 1 per 37 000 at ages 40-44 years. Among smokers, the cardiovascular mortality attributable to COC use was estimated to be about 1 per 100 000 users annually among women aged less than 35 years, and about 1 per 10 000 users annually among those above the age of 35 years.

Comment: The quality of evidence is upgraded by large magnitude of effect.

References

  1. Gillum LA, Mamidipudi SK, Johnston SC. Ischemic stroke risk with oral contraceptives: A meta-analysis. JAMA 2000 Jul 5;284(1):72-8. «PMID: 10872016»PubMed «DARE-12000008335»DARE
  2. The EMA’s Pharmacovigilance Risk Assessment Committee Pharmacovigilance Risk Assessment Committee (PRAC). PRAC confirms that benefits of all combined hormonal contraceptives (CHCs) continue to outweigh risks EMA/607314/2013. «http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/10/news_detail_001916.jsp&mid=WC0b01ac058004d5c1»1
  3. Lidegaard Ø, Løkkegaard E, Jensen A et al. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med 2012;366(24):2257-66. «PMID: 22693997»PubMed
  4. Farley TM, Meirik O, Chang CL et al. Combined oral contraceptives, smoking, and cardiovascular risk. J Epidemiol Community Health 1998;52(12):775-85. «PMID: 10396518»PubMed
  5. Roach RE, Helmerhorst FM, Lijfering WM et al. Combined oral contraceptives: the risk of myocardial infarction and ischemic stroke. Cochrane Database Syst Rev 2015;(8):CD011054. «PMID: 26310586»PubMed